March 11, 2005

How horrors of the plague made Europe safer from Aids scourge
By Russell Jenkins
::nobreak::LIFE was nasty, brutish and short when the waves of plague swept through Europe right up to the 18th century.

Scientific research now suggests, however, that the terrible suffering of our forebears means that a significant proportion of modern Europeans is resistant to Aids.

Research by two British biologists published in the Journal of Medical Genetics suggests that around 10 per cent of Europeans enjoy such protection as a direct result of the series of plagues that swept across the Continent from the Middle Ages onwards.

Biologists have known for some time that people carrying a particular genetic mutation, known as CCR5-delta32, remain free of the disease. The mutation prevents the HIV virus from entering the cells of the immune system.

It is also a continuing puzzle as to why the strains of HIV that have swept through Africa have made much less of an impression in Europe.

The new theory suggests that the CCR5 mutation was a by-product of the European plagues. The proportion of people carrying the natural resistance rises dramatically in Europe and particularly Scandinavia, where the figure is 14-15 per cent. It is relatively low in countries bordering the Mediterranean and not found at all in sub-Saharan Africa, Asia or among native Americans.

Christopher Duncan and Susan Scott, based at the University of Liverpool’s School of Biological Sciences, suggest that the natural protection from HIV can be attributed to the peculiar history of the plague from classical antiquity to 18th-century Denmark.

They have put forward a mathematical matrix showing how the frequency of genetic mutation rises with each stage of plague outbreak from the Black Death in 1347 to the Great Plague of London (1665-66) and beyond to the Plague of Copenhagen more than half a century later.

Using a computer model, they demonstrate how the pressure of natural selection increases the number of those carrying the resistance from around one in 20,000 at the time when plague devastated Europe, particularly France, during the mid-14th century to one in ten three centuries later.

Professor Duncan and Dr Scott, authors of The Return of the Black Death, published last year, are adamant that these plagues were not bubonic but epidemics of viral haemorrhagic fever that used the CCR5 receptor as the “entry port” into the immune system. These lethal haemorrhagic fevers — whose modern version is Ebola fever — are believed to have occurred as far back as antiquity.They were recorded in the Nile Valley from 1500 BC and in Mesopotamia (700-450BC), Athens (430BC), the plague of Justinian (AD 541-700) and the plagues of the early Islamic empire (AD 627-744).

If the plague struck a village carrying off half the population, those with the natural resistance became a higher proportion of the survivors. Then they handed it on to their descendants, who were also more likely to survive a plague.

Professor Duncan dismisses other theories which claim that resistance to Aids can be attributed to smallpox or bubonic plague. He is less sure that his work will have any practical impact on medical research and is not hopeful that the genetic mutation, can be reproduced artificially to create protection.




News
Published online: 11 March 2005; | doi:10.1038/news050307-15
Did Black Death boost HIV immunity in Europe?
Michael Hopkin
Experts argue over whether smallpox or plague should take the credit.


Deaths from plague in the Middle Ages may have left more people with a gene that guards against HIV.
© AP Photo
Devastating epidemics that swept Europe during the Middle Ages seem to have had an unexpected benefit - leaving 10% of today's Europeans resistant to HIV infection.

But epidemics of which disease? Researchers claimed this week that plague helped boost our immunity to HIV, but rival teams are arguing that the credit should go to smallpox.

What is clear is that something has boosted the prevalence of a mutation that helps protect against the virus. The mutation, which affects a protein called CCR5 on the surface of white blood cells, prevents HIV from entering these cells and damaging the immune system.

Around 10% of today's Europeans carry the mutation, a significantly higher proportion than in other populations. Why is it so common in Europe? One possibility is that it favours carriers by protecting them from disease. But geneticists know that the mutation, called CCR5-Delta32, appeared some 2,500 years ago - long before HIV reared its head.

"You need something that has been around for generation upon generation," explains Christopher Duncan of the University of Liverpool, UK, who led the latest analysis. Plague fits the bill, he and his colleagues conclude from a mathematical modelling study published in the Journal of Medical Genetics1.

You need something that has been around for generation upon generation.

Christopher Duncan
University of Liverpool, UK

Repeated outbreaks

Duncan's team points out that when the Black Death first struck, killing some 40% of Europeans between 1347 and 1350, only 1 person in 20,000 had the CCR5-Delta32 mutation. As the centuries wore on, repeated outbreaks, culminating in the Great Plague of London in the 1660s, have occurred in tandem with rises in the mutation's frequency.

Other experts are not convinced, however. A similar study2 published in 2003 suggests that it was smallpox that boosted the mutation's frequency. "Smallpox would still be my favoured hypothesis," comments Neil Ferguson, an infectious disease expert at Imperial College in London, who was not involved in the study.

Duncan counters that smallpox has only been a serious threat in Europe since the 1600s, which may not have been enough time to have such a big genetic effect. But Ferguson argues that the influence of smallpox over the centuries may have been underestimated, because it largely affected children.

Smallpox would still be my favoured hypothesis.

Neil Ferguson
Imperial College, London

"Smallpox seems the most parsimonious explanation," he adds. He points out that one major problem with Duncan's plague theory is that it requires a rethink of how plague was caused. If those with a virus-blocking mutation were more likely to survive, it follows that plague would have been caused by a virus. But the conventional view is that the plague epidemics of the Middle Ages were caused by a bacterium, Yersinia pestis.

Rats off the hook

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Duncan admits that his theory is difficult to prove. But he argues that the outbreaks are easier to explain if one assumes that plague was passed directly from person to person as a virus, rather than the 'bubonic plague' that was caused by bacteria carried by rats and their fleas. "Rats are absolutely in the clear for Europe," he argues.

If that's true, then Duncan can explain not only the mutation's average levels in Europe, but also the fact that people in Finland and Russia have the highest level, around 16%, whereas a mere 4% of Sardinians possess it.

He points out that outbreaks of feverish viral disease continued in Scandinavia and Russia for far longer than in the rest of the continent, reinforcing the mutation's status as a valuable asset. "It was mouldering on until about 1800 in northern Europe."